Reprogramming offers hope of safer stem cells

For the first time, specialised cells have been reprogrammed into the equivalent of embryonic stem cells without using genes that might trigger cancer. The new method, which places the proteins encoded by the reprogramming genes directly into the target cells, should be safer.

When Yamanaka repeated the trick the following year with human cells, it seemed that the goal of treating diseases like Parkinson’s using cells grown from a patient’s own skin cells might at last be within reach. But it was too risky to take cells grown from his iPS cells and transplant them into people.

First, the genes used for reprogramming are themselves known to trigger cancer, so if they were to reactivate could cause tumours to form. When retroviruses land in the chromosomes, they can also disrupt genes that normally keep cancers from forming, creating a second risk.

Now researchers led by Sheng Ding of the Scripps Research Institute in La Jolla, California, have taken genes out of the equation altogether. Since it is proteins that do the reprogramming, rather than the genes that make them, the researchers reasoned that they simply needed to get enough of the proteins into the target cells.

To do this, they attached each of the proteins to polyarginine, a molecule made of 11 copies of the amino acid arginine attached end-to-end. This positively charged molecule can readily cross cell membranes, dragging with it any attached protein.

Mouse fetuses

Ding’s team took cells called fibroblasts from the connective tissues of mouse fetuses and bathed them in a cocktail of the four polyarginine-tagged proteins for 12 hours, then they removed the reprogramming proteins for 36 hours, and repeated this cycle four times over. About two weeks later, they were able to extract colonies of iPS cells.

The reprogramming proteins are quickly broken down, and there is no genetic material left behind that might subsequently be reactivated. That means cells grown from the resulting iPS cells should not pose a major cancer risk.

“At face value, it looks very interesting,” says Rudolf Jaenisch, a stem cell biologist at the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts, who hopes that other teams will soon repeat the experiments.

First attempt

As yet, the technique is not as efficient as genetic reprogramming using genes and retroviruses – although it already works better than the adenovirus technique. Still, Ding is confident that he can boost the efficiency. “This is only the first attempt,” he says.

In the experiments so far, Ding’s team included a molecule called valproic acid that seems to improve the efficiency of reprogramming. He is now screening for more molecules that will further enhance the effect.

“I’m very happy to see that there will be other ways of developing genetically unaltered iPS cells,” says Andras Nagy of the Samuel Lunenfeld Research Institute at Mount Sinai Hospital in Toronto, Canada, who led one of the teams that reprogrammed cells using piggyBac.

While Nagy can get piggyBac to jump back out of his iPS cells, regulatory authorities considering the safety of experimental therapies are likely to remain nervous about cells that have been genetically manipulated. “The preference will be for proteins,” predicts Alan Trounson, who heads the California Institute for Regenerative Medicine in San Francisco.